The overall objective of the proposal is to perform pre-clinical evaluation of [18F](-)-JHU87522 ([18F]JHU), our novel unpublished radioligand with extraordinary properties for quantitative positron emission tomography (PET) imaging of the central nicotinic acethylcholine receptor (nAChR). There is an urgent need for PET imaging of the nAChR to study the role of the nicotinic system in Alzheimer's and Parkinson's diseases, schizophrenia, drug dependence and many other disorders. Greater understanding of the underlying mechanisms of the nicotinic system could direct the development of medications to treat these disorders. Central nAChRs also contribute to a variety of brain functions, including learning and memory, and they can mediate antinociception. Currently, only two radiotracers, 2-[18F]FA and 6-[18F]FA, are available for studying nAChRs in human brain using PET. However, the "slow" brain kinetics of these radiotracers hamper mathematical modeling and reliable measurement of kinetic parameters since it takes 5-7 hours of PET scanning for the tracer to reach a steady state. Another serious problem is the low binding potentials (BP) of 2- [18F]FA and 6-[18F]FA in all brain regions except the thalamus. In Preliminary Studies we synthesized [18F]JHU, a novel radiolabeled nAChR antagonist. In an initial baboon PET study [18F]JHU demonstrated exceptional imaging properties. Only 90 min of PET scanning with [18F]JHU was sufficient for robust quantification of nAChR in baboon brain. The BP values of [18F]JHU were 250% higher than those of 2-[18F]FA. The specific binding of [18F]JHU to nAChR in baboon was demonstrated in a blockade study with the selective nAChR agonist cytisine. These initial studies suggest that [18F]JHU is superior to 2-[18F]FA and 6-[18F]FA. This evaluation will become a basis for the future human studies. The specific aims are to: 1. Synthesize larger quantities of: a) the precursor for radiolabeling of [18F]JHU for this proposal and b) "cold" (-)-JHU87522 to use in future toxicology studies. 2. Characterize pharmacological, metabolic and radiation dosimetry profiles of [18F]JHU in mice. Blocking experiments are to determine if [18F]JHU selectively binds to central nAChRs. Metabolic studies will prove whether or not [18F]JHU generates radioactive metabolites that penetrate the blood-brain barrier. Radiation dosimetry experiments will provide evidence that [18F]JHU is safe for the future human studies. 3. Determine in the PET baseline and blocking studies in several baboons that [18F]JHU has optimally rapid brain kinetics, high binding potentials and specific in vivo binding to nAChRs. [unreadable] [unreadable] PUBLIC HEALTH REVELANCE: This preclinical evaluation will establish that [18F](-)-JHU87522 ([18F]JHU) has promise for human studies. Development of radioligands for positron emission tomography (PET) imaging of the nicotinic acethylcholine receptor (nAChR) is of great importance for studying the role of the nicotinergic system in neurodegenerative and neuropsychiatric disorders, drug dependence and a variety of other disorders as well as for developing nicotinic medications to treat these conditions. [unreadable] [unreadable] [unreadable]